Methods for treating psychosis associated with cocaine addiction with glucocorticoid receptor antagonists

ABSTRACT

This invention generally pertains to the field of psychiatry. In particular, this invention pertains to the discovery that agents which inhibit the binding of cortisol to its receptors can be used in methods for ameliorating pathologies or conditions associated with psychosis. These pathologies or conditions include psychotic major depression, schizoaffective disorders, Alzheimer&#39;s Disease and cocaine addiction. Mifepristone, a potent glucocorticoid receptor antagonist, can be used in these methods. The invention also provides a kit for the amelioration of psychosis in a human including a glucocorticoid receptor antagonist and instructional material teaching the indications, dosage and schedule of administration of the glucocorticoid receptor antagonist.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of Ser. No. 09/244,457, filedFeb. 4, 1999, now U.S. Pat. No. 6,150,349, which is a continuation ofPCT/US98/20906, filed Oct. 5, 1998, which is a continuation-in-part ofU.S. Provisional Application Ser. No. 60/060,973, filed Oct. 6, 1997.The aforementioned application is explicitly incorporated herein byreference in its entirety and for all purposes.

FIELD OF THE INVENTION

This invention generally pertains to the field of psychiatry. Inparticular, this invention pertains to the discovery that agents whichinhibit the binding of cortisol to its receptor can be used in methodsof ameliorating psychosis, including the psychotic component ofpathologies or conditions with psychotic symptoms.

INTRODUCTION

This invention is directed to a method for treating psychosis whosepathogenesis is related to glucocorticoid regulatory dysfunction. Thetypes of psychosis treated by the methods of the invention must bedistinguished from the older definition of psychosis, which referred toschizophrenia and manic states. Schizophrenia and manic states are notassociated with dysfunction of the glucocorticoid regulatory pathway andthere is no basis to believe that possibility. Thus, the treatmentmethods of the invention encompass the modem usage of the termpsychosis, i.e., non-schizophrenia and non-manic state associatedpsychosis.

There has been historic confusion in the definition of psychosis. Thisis, in part, based on a lack of understanding of a commonpathophysiologic mechanism causing psychosis in various conditions. Forexample, Oberlander, et al., WO 98/26785, teaches use of ananti-glucocorticoid to treat schizophrenia and manic states. However,schizophrenia and manic states are are believed to be the result ofabnormal nerve structure, i.e., “hard-wiring” problems. In contrast, itis believed that the pathophysiology of psychosis (the term used in itsmodem sense, as used in the instant invention) is related toneurochemical (glucocorticoid regulatory) problems. This theory isextended by the instant invention, in which it was surprisinglydiscovered that agents which inhibit the binding of cortisol to itsreceptor can be used to treat psychosis.

Today it is known that psychotic patients can be distinguished fromother psychiatric problems in that they have a glucocorticoid regulatorydysfunction. In contrast, patients with schizophrenia and manic statesdo not have glucocorticoid regulatory dysfunction (see, e.g., Rothschild(1982) Br. J. Psychiatry 141:471-474; Clower (1986) J. Clin.Psychopharmacol. 6:363-365). Thus, schizophrenia and manic states arenot within the scope of the definition of “psychosis” (as defined eitherby the medical profession, or, as used herein), and thus are not treatedby the methods of the invention.

In most species, including man, the physiological glucocorticoid iscortisol (hydrocortisone). Glucocorticoids are secreted in response toACTH (corticotropin), which shows both circadian rhythm variation andelevations in response to stress and food. Cortisol levels areresponsive within minutes to many physical and psychological stresses,including trauma, surgery, exercise, anxiety and depression. Cortisol isa steroid and acts by binding to an intracellular, glucocorticoidreceptor (GR). In man, glucocorticoid receptors are present in twoforms: a ligand-binding GR-alpha of 777 amino acids; and, a GR-betaisoform which differs in only the last fifteen amino acids. The twotypes of GR have high affinity for their specific ligands, and areconsidered to function through the same transduction pathways.

The biologic effects of cortisol, including those caused byhypercortisolemia, can be modulated at the GR level using receptorantagonists. Several different classes of agents are able to block thephysiologic effects of GR-agonist binding. These antagonists includecompositions which, by binding to GR, block the ability of an agonist toeffectively bind to and/or activate the GR. One such known GRantagonist, mifepristone, has been found to be an effectiveanti-glucocorticoid agent in humans (Bertagna (1984) J. Clin.Endocrinol. Metab. 59:25). Mifepristone binds to the GR with highaffinity, with a K of dissociation ≦10⁻⁹ M (Cadepond (1997) Annu. Rev.Med. 48:129).

Patients with some forms of psychiatric illnesses have been found tohave increased levels of cortisol (Krishnan (1992) Prog.Neuro-Psychopharrnacol. & Biol. Psychiat. 16:913-920). For example, somepatients with depressed mood have had their mood improve with treatmentswhich lower the levels of cortisol. In some individuals, reversingincreased cortisol levels using inhibitors of steroid biosynthesis canbe effective in treating depression (Murphy (1991) J. Steroid Biochem.Mol. Biol. 39:239; Murphy (1991) J. Clin. Psychopharmcol. 11:121; Dhar(1989) Clin. Invest. Med. 12:B27). Alternatively, some depressedindividuals can be responsive to treatments which block the effect ofcortisol, as by administering GR antagonists (Van Look (1995) HumanReproduction Update 1:19-34). In one study, a patient with depressionsecondary to Cushing's Syndrome (hyperadrenocorticism) was responsive toa high dose, up to 1400 mg per day, of GR antagonist mifepristone(Nieman (1985) J. Clin Endocrinol. Metab. 61:536). Another study whichused mifepristone to treat Cushing's syndrome found that it improved thepatients' conditions, including their psychiatric status (Chrousos, pp273-284, In: Baulieu, ed. The Antiprogestin Steroid RU 486 and HumanFertility Control. Plenum Press, New York (1989), Sartor (1996) Clin.Obstetrics and Gynecol. 39:506-510). Mifepristone has been used to treatmajor depression. Using from about 2.5 to 4.4 mg/kg per day for periodsup to eight weeks, one group found that four patients with chronicsevere depression, who were resistant to conventional therapies,responded to treatment (Murphy (1993) J. Psychiatr. Neurosci. 18:209).

Psychosis has also been associated with Cushing's syndrome (Gerson(1985) Can. J. Psychiatry 30:223-224; Saad (1984) Am. J. Med.76:759-766). Mifepristone has been used to treat acute psychiatricdisturbances secondary to Cushing's syndrome. One study showed that arelatively high dose of mifepristone (400 to 800 mg per day) was usefulin rapidly reversing acute psychosis in patients with severe CushingSyndrome due to adrenal cancers and ectopic secretion of ACTH from lungcancer (Van der Lely (1991) Ann. Intern. Med. 114:143; Van der Lely(1993) Pharmacy World & Science 15:89-90; Sartor (1996) supra).

Psychotic major depression has long been recognized as a distinctpsychiatric illness, having both psychotic and depressive components. Ina differential diagnosis, it is important that psychotic majordepression be distinguished from nonpsychotic major depression, becauseeffective treatments and patterns of response to pharmacologic therapiesfor psychotic major depression are very different from those relating tonon-psychotic major depression. Successful treatment depends on theaccuracy of the initial diagnosis. (Glassman (1981) Arch. Gen.Psychiatry 38:424-427, Schatzberg (1992) Am. J. Psychiatr. 149:733-745,Schatzberg (1988) Annals N.Y. Acad. of Sci.537:462). Psychotic majordepression is very common. It has been estimated that twenty fivepercent of depressed patients admitted to the hospital have psychoticmajor depression (Coryell (1984) J. Nerv. Ment. Dis. 172:521).

Before this invention, there was to fast-acting effective treatmentwithout significant side effects for the treatment of psychosis or thepsychotic component of illnesses and conditions associated withpsychosis, such as psychotic major depression. Individuals sufferingfrom psychotic major depression have a low placebo response rate andrespond poorly to antidepressant therapy alone, i.e., without concurrenttreatment with antipsychotic medication (Glassman (1975) Am. J.Psychiatry 132:716-719; Avery (1979) Am. J. Psychiatry 135:559-562).While psychotic depression can respond to electroconvulsive therapy(ECT), this form of treatment is controversial, can have significantside effects, has a relatively slow response rate and has a high levelof related morbidity. Similarly, another commonly used treatment forpsychotic major depression, a combination therapy of currently availableantipsychotic and antidepressant medications, has a slow onset of actionand a relatively high rate of morbidity (Minter (1979) J. Nerv. Ment.Dis. 167:726-733).

Thus, there exists a great need for a more effective and safer treatmentfor psychosis and illnesses and conditions associated with psychosis,including psychotic major depression. There is a great need for a newtreatment for psychotic major depression which has a quick responsetime, has few side effects, decreases the amount of time a patient mustbe institutionalized and has a lower rate of morbidity. Furthermore,there exists a variety of conditions which have a psychotic element forwhich there is no known cure or effective treatment. These includeschizoaffective disorder, Alzheimer's Disease and cocaine addiction.Thus, there exists a great need for a safe and effective treatment forthese conditions. The present invention fulfills these and other needs.

SUMMARY OF THE INVENTION

The invention is directed to a method of treating psychosis associatedwith glucocorticoid related dysfunction by administration of an amountof a glucocorticoid receptor antagonist effective to ameliorate thepsychosis, with the proviso that the patient not be suffering fromCushing's Syndrome. In alternative embodiments of this method, thepsychosis is associated with psychotic major depression, schizoaffectivedisorder, Alzheimer's Disease and cocaine addiction.

In further embodiments, the glucocorticoid receptor antagonist used inthe methods can comprise a steroidal skeleton with at least onephenyl-containing moiety in the 11-beta position of the steroidalskeleton. The phenyl-containing moiety in the 11-beta position of thesteroidal skeleton can be a dimethylaminophenyl moiety.

In alternative embodiments of the invention, the glucocorticoid receptorantagonist can comprise mifepristone (RU486), RU009 or RU044. Theglucocorticoid receptor antagonist can be administered in a daily amountof between about 8 to 20 mg per kilogram of body weight per day, or, ina daily amount of about 8 to 12 mg per kilogram of body weight per day.The glucocorticoid receptor antagonist can be administered for aboutfour days. It can be administered in a daily amount of about 600 mg perday. The administration can be once per day. Its mode of administrationcan be oral or transdermal.

In a preferred embodiment, the invention relates to a method ofameliorating psychotic depression comprising administering amifepristone in a daily amount of about 8 to 12 mg per kilogram of bodyweight per day, wherein the administration continues for a period ofabout four days.

The invention also relates to a kit for the amelioration of psychosis ina human, the kit comprising: a glucocorticoid receptor antagonist; and,an instructional material teaching the indications, dosage and scheduleof administration of the glucocorticoid receptor antagonist. The kit'sinstructional material can indicate that the glucocorticoid receptorantagonist can be administered in a daily amount of about 8 to 12 mg perkilogram of body weight per day. The instructional material can indicatethat the administration of the glucocorticoid receptor antagonist cancontinue for a period of about four days.

In one embodiment, the kit is for the amelioration of psychosis as acomponent of psychotic major depression and the instructional materialindicates that the glucocorticoid receptor antagonist can be used forthe treatment of psychotic major depression. In a preferred embodiment,the kit's glucocorticoid receptor antagonist is mifepristone, which canbe in tablet form.

The invention also relates to a novel means of diagnosing and assessingtreatments for psychosis using color-word recognition tests. In oneembodiment, the Stroop Color and Word Test, or variations thereof, isused to objectively determine whether an individual is psychotic, thedegree of psychosis and the efficacy of an antipsychotic treatmentregimen. The invention also provides a color-word test to differentiallydiagnose psychotic major depression from non-psychotic major depression.

A further understanding of the nature and advantages of the presentinvention is realized by reference to the remaining portions of thespecification, the figures and claims.

All publications, patents and patent applications cited herein arehereby expressly incorporated by reference for all purposes.

DEFINITIONS

The term “ameliorating” or “ameliorate” refers to any indicia of successin the treatment of a pathology or condition, including any objective orsubjective parameter such as abatement, remission or diminishing ofsymptoms or an improvement in a patient's physical or mental well-being.Amelioration of symptoms can be based on objective or subjectiveparameters; including the results of a physical examination and/or apsychiatric evaluation. For example, a clinical guide to monitor theeffective amelioration of a psychiatric disorder, such as psychosis ordepression, is found in the Structured Clinical Interview for DSM-IVAxis I mood disorders (“SCID-P”) (see fourth edition of Diagnostic andStatistical Manual of Mental Disorders (1994) Task Force on DSM-IV,American Psychiatric Association (“DSM-IV”); Kaplan, Ed. (1995)Comprehensive Textbook of Psychiatry/VI, vol. 1, sixth ed., pp 621-627,Williams & Wilkins, Balt., Md.).

The term “glucocorticoid receptor antagonist” refers to any compositionor compound which partially or completely inhibits (antagonizes) thebinding of a glucocorticoid receptor (GR) agonist, such as cortisol, orcortisol analogs, synthetic or natural, to a GR. A “glucocorticoidreceptor antagonist” also refers to any composition or compound whichinhibits any biological response associated with the binding of a GR toan agonist.

The term “glucocorticoid receptor” (“GR”) refers to a family ofintracellular receptors also referred to as the cortisol receptor, whichspecifically bind to cortisol and/or cortisol analogs. The term includesisoforms of GR, recombinant GR and mutated GR.

The term “cortisol” refers to a family of compositions also referred tohydrocortisone, and any synthetic or natural analogues thereof.

The term “mifepristone” refers to a family of compositions also referredto as RU486, or RU38.486, or17-beta-hydroxy-11-beta-(4-dimethyl-aminophenyl)-17-alpha-(1-propynyl)-estra-4,9-dien-3-one),or11-beta-(4dimethylaminophenyl)-17-beta-hydroxy-17-alpha-(1-propynyl)-estra-4,9-dien-3-one),or analogs thereof, which bind to the glucocorticoid receptor, typicallywith high affinity, and inhibit the biological effectsinitiated/mediated by the binding of any cortisol or cortisol analogueto a receptor. Chemical names for RU-486 vary; for example, RU486 hasalso been termed:11B-[p-(Dimethylamino)phenyl]-17B-hydroxy-17-(1-propynyl)-estra-4,9-dien-3-one;11B-(4-dimethyl-aminophenyl)-17B-hydroxy-17A-(prop-1-ynyl)-estra-4,9-dien-3-one;17B-hydroxy-11B-(4-dimethylaminophenyl-1)-17A-(propynyl-1)-estra-4,9-diene-3-one;17B-hydroxy-11B-(4-dimethylaminophenyl-1)-17A-(propynyl-1)-E;(11B,17B)-11[4-dimethylamino)-phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one;and11B-[4-(N,N-dimethylaino)phenyl]-17A-(prop-1-ynyl)-D-4,9-estradiene-17B-ol-3-one.

The term “psychotic” as used herein refers to a psychiatric condition inits broadest sense, as defined in the DSM-WV (Kaplan, ed. (1995) supra)and described below. The term “psychotic” has historically received anumber of different definitions, ranging from narrow to broadlydescribed. A psychotic condition can include delusions or prominenthallucinations, including prominent hallucinations that the individualrealizes are hallucinatory experiences, and those with hallucinationsoccurring in the absence of insight into their pathological nature.Finally, the term includes a psychotic condition characterized by a lossof ego boundaries or a gross impairment in reality testing. Unlike thisdefinition, which is broad and based primarily on symptoms,characterization of psychosis in earlier classifications (e.g., DSM-IIand ICD-9) were more inclusive and focused on the severity of functionalimpairment (so that a mental disorder was termed “psychotic” if itresulted in “impairment” that grossly interferes with the capacity tomeet ordinary demands of life). Different disorders which have apsychotic component comprise different aspects of this definition of“psychotic.” For example, in schizophreniform disorder, schizoaffectivedisorder and brief psychotic disorder, the term “psychotic” refers todelusions, any prominent hallucinations, disorganized speech, ordisorganized or catatonic behavior. In psychotic disorder due to ageneral medical condition and in substance-induced psychotic disorder,“psychotic” refers to delusions or only those hallucinations that arenot accompanied by insight. Finally, in delusional disorder and sharedpsychotic disorder, “psychotic” is equivalent to “delusional” (seeDSM-IV, supra, page 273).

Objective tests can be also be used to determine whether an individualis psychotic and to measure and assess the success of a particulartreatment schedule or regimen. For example, measuring changes incognitive ability aids in the diagnosis and treatment assessment of thepsychotic patient. Any test known in the art can be used, such as theso-called “Wallach Test,” which assesses recognition memory (see below,Wallach (1980) J. Gerontol. 35:371-375). For example, as described inExample 1, when the Wallach Recognition Test was used to measure thedegree of amelioration of psychosis in the study's subjects, on theaverage, test subjects identified fewer distracters over words they hadactually heard before. The number of distracting words mis-identified aswords actually presented in the test declined between 25% and 100% aftertreatment. Another example of an objective text which can be used todetermine whether an individual is psychotic and to measure efficacy ofan anti-psychotic treatment is the Stroop Color and Word Test (“StroopTest”) (see Golden, C. J., Cat. No. 30150M, In A Manualfor Clinical andExperimental Uses, Stoelting, Wood Dale, Ill.). The Stroop Test is anobjective neuropsychiatric test that can differentiate betweenindividuals with psychosis and those without, and is described in detailbelow.

The term “psychosis” refers to a psychiatric symptom, condition orsyndrome in its broadest sense, as defined in the DSM-IV (Kaplan, ed.(1995) supra), comprising a “psychotic” component, as broadly definedabove. The term psychosis can refer to a symptom associated with ageneral medical condition, a disease state or other condition, such as aside effect of drug abuse (a substance-induced disorder) or as a sideeffect of a medication. Alternatively, the term psychosis can refer to acondition or syndrome not associated with any disease state, medicalcondition, drug intake or the like. Psychosis is typically defined as amental disorder or condition causing gross distortion or disorganizationof a person's mental capacity, affective response, and capacity torecognize reality, communicate, and relate to others to the degree ofinterfering with his capacity to cope with the ordinary demands ofeveryday life.

Historically, the term “psychosis” was sometimes used to describeschizophrenia and manic states (these conditions are separatelydescribed in the DSM-IV, supra). However, the current medical view, asembraced by the DSM-IV, supra, does not include these psychiatricconditions as including psychosis. There is a physiologic basis for thisdiscrimination, which was recognized as early as Rothschild, et al.(1982) “The dexamethasone suppression test as a discriminator amongsubtypes of psychotic patients,” Br. J. Psychiatry 141:471-474; and,Clower (1986) “The 2-mg dexamethasone suppression test indifferentiating major depression with psychosis from schizophrenia,” J.Clin. Psychopharmacol. 6:363-365. The dexamethasone suppression (DS)test indicates a dysfunction in the glucocorticoid regulatory feedbackpathway, which is controlled by the hypothalamic-pituitary-adrenal (HPA)axis (non-responsiveness in the test means a patient cannot suppress(negatively feedback) cortisol production when challenged with a testdose of a synthetic glucocorticoid, dexamethasone). Most psychoticpatients have a glucocorticoid regulatory dysfunction (as indicated bynon-responsiveness in the DS test). In contrast, patients with, e.g.,schizophrenia (including those historically described as “psychoticschizophrenics”) and manic states, do not have glucocorticoid regulatorydysfunction (as indicated by responsiveness in the DS test). It iswidely believed that schizophrenia and manic states are caused byabnormal nerve structure, i.e., a “hard-wiring” problem. In contrast, itis believed that the pathophysiology of psychosis is related toneurochemical problems, particularly, HPA axis regulatory dysfunction(this theory is extended by the instant invention, in which it wasdiscovered that that agents which inhibit the binding of cortisol to itsreceptor will treat psychosis). Thus, schizophrenia and manic states arenot within the scope of the definition of “psychosis” (as defined eitherby the medical profession, or, as used herein), and thus are not treatedby the methods of the invention.

The term “psychotic major depression,” also referred to as “psychoticdepression” (Schatzberg (1992) Am. J. Psychiatry 149:733-745),“psychotic (delusional) depression” (Ibid.), “delusional depression”(Glassman (1981) supra) and, “major depression with psychotic features”(see the DSM-III-R), refers to a distinct psychiatric disorder whichincludes both depressive and psychotic features. Individuals manifestingboth depression and psychosis, i.e. psychotic depression, are hereinreferred to as “psychotic depressives.” It has been long-recognized inthe art as a distinct syndrome, as described, for example, by Schatzberg(1992) supra. Illustrative of this distinctness are studies which havefound significant differences between patients with psychotic andnonpsychotic depression in glucocorticoid activity,dopamine-beta-hydroxylase activity, levels of dopamine andserotonin-metabolites, sleep measures and ventricle to brain ratios.Psychotic depressives respond very differently to treatment compared toindividuals with other forms of depression, such as “non-psychotic majordepression.” Psychotic depressives have a low placebo response rate anda respond poorly to antidepressant therapy alone (without concurrentanti-psychotic treatment). Psychotic depressives are markedlyunresponsive to tricyclic (anti-depressive) drug therapy (Glassman, etal. (1975) supra). While psychotic depressives can respond toelectroconvulsive therapy (ECT), their response time is relatively slowand the ECT has a high level of related morbidity. Clinicalmanifestations and diagnostic parameters of “psychotic major depression”is described in detail in the DSM-IV (Kaplan, ed. (1995) supra). Thus,due to its unique pathophysiology, high rate of morbidity and responseto treatment, there is great practical need to differentially diagnoseand specifically treat psychotic major depression as compared tonon-psychotic depression.

DETAILED DESCRIPTION OF THE INVENTION

This invention pertains to the discovery that agents that can inhibit abiological response caused by an agonist-occupied glucocorticoidreceptor (GR) are effective for ameliorating the mental disorder, orsyndrome, of psychosis. Because the condition of psychosis can beassociated with or caused by a variety of conditions and diseaseprocesses, the methods of the invention also are used to ameliorate thepsychotic component of pathologies or conditions involving psychosis.These pathologies or conditions include psychotic major depression,schizoaffective disorders, Alzheimer's Disease, cocaine addiction, drugside effects and the like.

In one embodiment, the methods of the invention use agents that act asGR antagonists, blocking the interaction of cortisol with GR, therebyameliorating psychosis. In another embodiment, mifepristone, a potent GRantagonist, is used in methods to ameliorate psychosis. The inventionprovides a new, effective treatment for psychotic major depression whichis relatively fast, has fewer side effects, decreases the amount of timea patient must be institutionalized and has a lower rate of morbiditywhen compared to alternative treatments.

As psychosis can be manifested as a mental illness in the form of asyndrome or as an element of a disease process or other condition,various means of diagnosing and assessing the success of treatment,i.e., the success and extent the psychosis is ameliorated, are set forthbelow. These means include classical psychological evaluations andvarious laboratory procedures. As the methods of the invention includeuse of any means to inhibit the biological effect of a GR to amelioratepsychosis, illustrative compounds and compositions which can be used totreat psychosis are also set forth. Routine procedures that can be usedto identify further compounds and compositions able to block thebiological response caused by a GR-agonist interaction for use inpracticing the methods of the invention are also described. As theinvention provides for administering these compounds and compositions aspharmaceuticals, routine means to determine GR antagonist drug regimensand formulations to practice the methods of the invention are set forthbelow.

1. General Laboratory Procedures

A number of general laboratory tests can be used to assist in thediagnosis, progress and prognosis of the patient. Monitoring ofparameters such as blood cortisol, drug metabolism, brain function andthe like may be needed because all patients metabolize and react todrugs uniquely. In addition, such monitoring may be important becauseeach GR antagonist has different pharmnacokinetics. Different diseaseconditions may require different dosage regimens and formulations. Suchprocedures are well described in the scientific and patent literature. Afew illustrative examples are set forth below.

a. Determining Blood Cortisol Levels

Because levels of blood cortisol have been associated with psychosis anddepression, monitoring blood cortisol levels can be a useful laboratorytest to aid in the diagnosis, treatment and prognosis of the patient. Awide variety of laboratory tests exist that can be used to determinewhether an individual is normal, hypo- or hypercortisolemic.Immunoassays such as radioimmunoassays are commonly used because theyare accurate, easy to do and relatively cheap. Because levels ofcirculating cortisol is an indicator of adrenocorticol function, avariety of stimulation and suppression tests, such as ACTH Stimulation,ACTH Reserve, Dexamethasone Suppression, can also provide diagnostic,prognostic or other information to be used adjunctively in the methodsof the invention.

One such assay available in kit form is the radioinimunoassay availableas “Double Antibody Cortisol Kit™” (Diagnostic Products Corporation, LosAngeles, Cali., (1984) Acta Psychiatr. Scand. 70:239-247). This test isa competitive radioimmunoassay in which ¹²⁵I-labeled cortisol competeswith cortisol from an clinical sample for antibody sites. In this test,due to the specificity of the antibody and lack of any significantprotein effect, serum and plasma samples require neither preextractionnor predilution. This assay is described in further detail in Example 1,below.

i. Determining Blood/Urine Mifepristone Levels

Because a patient's metabolism, clearance rate, toxicity levels, etc.differs with variations in underlying primary or secondary diseaseconditions, drug history, age, general medical condition and the like,it may be necessary to measure blood and urine levels of GR antagonist.Means for such monitoring are well described in the scientific andpatent literature. As in one embodiment of the invention mifepristone isadministered to ameliorate psychosis, an illustrative example ofdetermining blood and urine mifepristone levels is set forth below.

ii. Other Laboratory Procedures

Because psychosis can be associated with a variety of diseases,conditions, and drug effects, a number of additional laboratory testscan be used adjunctively in the methods of the invention to assist indiagnosis, treatment efficacy, prognosis, toxicity and the like. Forexample, as increased hypercortisolemia has been associated withpsychosis and depression, diagnosis and treatment assessment can beaugmented by monitoring and measuring glucocorticoid-sensitivevariables, including but limited to fasting blood sugar, blood sugarafter oral glucose administration, plasma concentrations thyroidstimulating hormone (TSH), corticosteroid-binding globulin, luteinizinghormone (LH), testosterone-estradiol-binding globulin, and/or total andfree testosterone. Laboratory tests monitoring and measuring GRantagonist metabolite generation, plasma concentrations and clearancerates, including urine concentration of antagonist and metabolites, mayalso be useful in practicing the methods of the invention. For example,mifepristone has two hydrophilic, N-monomethylated and N-dimethylated,metabolites. Plasma and urine concentrations of these metabolites (inaddition to RU486) can be determined using, for example, thin layerchromatography, as described in Kawai (1987) Pharmacol. and ExperimentalTherapeutics 241:401-406.

2. Glucocorticoid Recepetor Antagonists to Treat Psychosis

The invention provides for methods of treating psychosis utilizing anycomposition or compound that can block a biological response associatedwith the binding of cortisol or a cortisol analogue to a GR. Antagonistsof GR activity utilized in the methods of the invention are welldescribed in the scientific and patent literature. A few illustrativeexamples are set forth below.

a. Steroidal Anti-Glucocorticoids as GR Antagonists

In one embodiment of the invention, steroidal glucocorticoid antagonistsare administered for the amelioration of psychosis. Steroidalantiglucocorticoids can be obtained by modification of the basicstructure of glucocorticoid agonists, i.e., varied forms of the steroidbackbone. The structure of cortisol can be modified in a variety ofways. The two most commonly known classes of structural modifications ofthe cortisol steroid backbone to create glucocorticoid antagonistsinclude modifications of the 11-beta hydroxy group and modification ofthe 17-beta side chain. (Lefebvre (1989) J. Steroid Biochem.33:557-563).

i. Removal or Substitution of the 11-beta Hydroxy Group

In another embodiment of the invention, glucocorticoid agonists withmodified steroidal backbones comprising removal or substitution of the11-beta hydroxy group are administered. This class includes naturalantiglucocorticoids, including cortexolone, progestertone andtestosterone derivatives, and synthetic compositions, such asmifepristone (Lefebvre, et al. (1989) Ibid). Preferred embodiments ofthe invention include all 11-beta-aryl steroid backbone derivativesbecause these compounds are devoid of progesterone receptor (PR) bindingactivity (Agarwal (1987) FEBS 217:221-226). Another preferred embodimentcomprises an 11-beta phenyl-aminodimethyl steroid backbone derivative,i.e., mifepristone, which is both an effective anti-glucocorticoid andanti-progesterone agent. These compositions act as reversibly-bindingsteroid receptor antagonists For example, when bound to a 11-betaphenyl-aminodimethyl steroid, the steroid receptor is maintained in aconformation that cannot bind its natural ligand, such as cortisol inthe case of GR (Cadepond, et al., (1997), supra).

Synthetic 11-beta phenyl-aminodimethyl steroids include mifepristone,also known as RU486, or17-beta-hydrox-11-beta-(4-dimethyl-aminophenyl)17-alpha-(1propynyl)estra-4,9-dien-3-one).It has been shown to be a powerful antagonist of both the progesteroneand glucocorticoid (GR) receptors: Another 11-beta phenyl-aminodimethylsteroids shown to have GR antagonist effects includes RU009 (RU39.009),11-beta-(4dimethyl-amninoethoxyphenyl)-17-alpha-(propynyl-17beta-hydroxy-4,9-estradien-3-one)(see Bocquel (1993) J. Steroid Biochem. Molec. Biol. 45:205-215).Another GR antagonist related to RU486 is RU044 (RU43.044)17-beta-hydrox-17-alpha-19-(4-methylphenyl)-androsta-4,9(11)-dien-3-one) (Bocquel (1993) supra). See also Teutsch (1981)Steroids 38:651-665; U.S. Pat. Nos. 4,386,085 and 4,912,097.

One embodiment includes compositions containing the basic glucocorticoidsteroid structure which are irreversible anti-glucocorticoids. Suchcompounds include alpha-keto-methanesulfonate derivatives of cortisol,including cortisol-21-mesylate (4-pregnene-11-beta, 17-alpha,21-triol-3,20-dione-21-methane-sulfonate anddexamethasone-21-mesylate(16-methyl-9 alpha-fluoro-1,4-pregnadiene-11beta, 17-alpha,21-triol-3,20-dione-21-methane-sulfonate). See Simons(1986) J. Steroid Biochem. 24:25-32 (1986); Mercier(1986) J. SteroidBiochem. 25:11-20; U.S. Pat. No. 4,296,206.

ii. Modification of the 17-beta Side Chain Group

Steroidal antiglucocorticoids which can be obtained by variousstructural modifications of the 17-beta side chain are also used in themethods of the invention. This class includes syntheticantiglucocorticoids such as dexamethasone-oxetanone, various 17,21-acetonide derivatives and 17-beta-carboxamide derivatives ofdexamethasone (Lefebvre (1989) supra; Rousseau (1979) Nature279:158-160).

iii. Other Steroid Backbone Modifications

GR antagonists used in the various embodiments of the invention includeany steroid backbone modification which effects a biological responseresulting from a GR-agonist interaction. Steroid backbone antagonistscan be any natural or synthetic variation of cortisol, such as adrenalsteroids missing the C-19 methyl group, such as19-nordeoxycorticosterone and 19-norprogesterone (Wynne (1980)Endocrinology 107:1278-1280).

In general, the 11-beta side chain substituent, and particularly thesize of that substituent, can play a key role in determining the extentof a steroid's antiglucocorticoid activity. Substitutions in the A ringof the steroid backbone can also be important. 17-hydroxypropenyl sidechains generally decrease antiglucocorticoidal activity in comparison to17-propinyl side chain containing compounds.

b. Non-Steroidal Anti-Glucocorticoids as Antagonists

Non-steroidal glucocorticoid antagonists are also used in the methods ofthe invention to ameliorate psychosis. These include synthetic mimeticsand analogs of proteins, including partially peptidic, pseudopeptidicand non-peptidic molecular entities: For example, oligomericpeptidomimetics useful in the invention include (alpha-beta-unsaturated)peptidosulfonamides, N-substituted glycine derivatives, oligocarbamates, oligo urea peptidomimetics, hydrazinopeptides, oligosulfonesand the like (de Bont (1996) Bioorganic & Medicinal Chem. 4:667-672).The creation and simultaneous screening of large libraries of syntheticmolecules can be carried out using well-known techniques incombinatorial chemistry, for example, see van Breemen (1997) Anal Chem69:2159-2164; Lam (1997) Anticancer Drug Des 12:145-167 (1997). Designof peptidomimetics specific for GR can be designed using computerprograms in conjunction with combinatorial chemistry (combinatoriallibrary) screening approaches (Murray (1995) J. of Computer-Aided Molec.Design 9:381-395); Bohm (1996) J. of Computer-Aided Molec. Design10:265-272). Such “rational drug design” can help develop peptideisomerics and conformers including cycloisomers, retro-inverso isomers,retro isomers and the like (as discussed in Chorev (1995) TibTech13:438-445).

c. Identifying Glucocorticoid Receptor Antagonists

Because any GR antagonist can be used for the amelioration of psychosisin the methods of the invention, in addition to the compounds andcompositions described above, additional useful GR antagonists can bedetermined by the skilled artisan. A variety of such routine, well-knownmethods can be used and are described in the scientific and patentliterature. They include in vitro and in vivo assays for theidentification of additional GR antagonists. A few illustrative examplesare described below.

One assay that can be used to identify a GR antagonist of the inventionmeasures the effect of a putative GR antagonist on tyrosineamino-transferase activity in accordance with the method of Granner(1970) Meth. Enzymol. 15:633. This analysis is based on measurement ofthe activity of the liver enzyme tyrosine amino-transferase (TAT) incultures of rat hepatoma cells (RHC). TAT catalyzes the first step inthe metabolism of tyrosine and is induced by glucocorticoids (cortisol)both in liver and hepatoma cells. This activity is easily measured inraw extracts. TAT converts the amino group of tyrosine to 2-oxoglutaricacid, and p-hydroxyphenylpyruvate is also formed, which is converted tothe more stable p-hydroxybenzaldehyde in alkaline solution, which can bemeasured at 331 nm. The putative GR antagonist is co-administered withcortisol to whole liver, in vivo or ex vivo, or hepatoma cells or cellextracts. A compound is identified as a GR antagonist when itsadministration decreases the amount of induced TAT activity, as comparedto control (i.e., only cortisol or GR agonist added) (see also Shirwany(1986) “Glucocorticoid regulation of hepatic cytosolic glucocorticoidreceptors in vivo and its relationship to induction of tyrosineaminotransferase,” Biochem. Biophys. Acta 886:162-168).

Further illustrative of the many assays which can be used to identifycompositions utilized in the methods of the invention, in addition tothe TAT assay, are assays based on glucocorticoid activities in vivo.For example, assays that assess the ability of a putative GR antagonistto inhibit uptake of ³H-thyrridine into DNA in cells which arestimulated by glucocorticoids can be used. Alternatively, the putativeGR antagonist can complete with ³H-dexamethasone for binding to ahepatoma tissue culture GR (see, for example, Choi (1992) “Enzymeinduction and receptor-binding affinity of steroidal 20-carboxamides inrat hepatoma tissue culture cells,” Steroids 57:313-318). As anotherexample, the ability of a putative GR antagonist to block nuclearbinding of ³H-dexamethasone-GR complex can be used (Alexandrova (1992)“Duration of antagonizing effect of RU486 on the agonist induction oftyrosine aminotransferase via glucocorticoid receptor,” J. SteroidBiochem. Mol. Biol. 41:723-725). To further identify putative GRantagonists, kinetic assays able to discriminate between glucocorticoidagonists and antagonists by means of receptor-binding kinetics can alsobe used (as described in Jones (1982) Biochem J. 204:721-729).

In another illustrative example, the assay described by Daune (1977)Molec. Pharm. 13:948-955, and in U.S. Pat. No. 4,386,085, can be used toidentify anti-glucocorticoid activity. Briefly, the thymocytes ofsurrenalectomized rats are incubated in nutritive medium containingdexamethasone with the test compound (the putative GR antagonist) atvarying concentrations. ³H-uridine is added to the cell culture, whichis further incubated, and the extent of incorporation of radiolabel intopolynucleotide is measured. Glucocorticoid agonists decrease the amountof ³H-uridine incorporated. Thus, a GR antagonist will oppose thiseffect.

For additional compounds that can be utilized in the methods of theinvention and methods of identifying and making such compounds, see U.S.Pat. Nos. 4,296,206 (see above); 4,386,085 (see above); 4,447,424;4,477,445; 4,519,946; 4,540,686; 4,547,493; 4,634,695; 4,634,696;4,753,932; 4,774,236; 4,808,710; 4,814,327; 4,829,060; 4,861,763;4,912,097; 4,921,638; 4,943,566; 4,954,490; 4,978,657; 5,006,518;5,043,332; 5,064,822; 5,073,548; 5,089,488; 5,089,635; 5,093,507;5,095,010; 5,095,129; 5,132,299; 5,166,146; 5,166,199; 5,173,405;5,276,023; 5,380,839; 5,348,729; 5,426,102; 5,439,913; and 5,616,458;and WO 96/19458, which describes non-steroidal compounds which arehigh-affinity, highly selective modulators (antagonists) for steroidreceptors, such as 6-substituted-1,2-dihydro N-1 protected quinolines.

3. Diagnosing and Assessing Conditions and Illnesses Involving Psychosis

Psychosis can be manifested as a mental illness in the form of asyndrome or as an element of a variety of disease processes. There arevarious means to diagnose these various forms of psychosis and assessthe success of treatment. These means include classical psychologicalevaluations in addition to the various laboratory procedures describedabove. Such means are well-described in the scientific and patentliterature, and some illustrative examples are provided below.

a. Assessing and Diagnosing Psychosis

The psychosis ameliorated in the methods of the invention encompasses abroad range of mental conditions and symptoms, as broadly described inthe DSM-IV (Kaplan, ed. (1995) supra). Psychosis can refer to a symptomassociated with a general medical condition, a disease state or othercondition, such as a side effect of drug abuse (a substance-induceddisorder) or as a side effect of a medication. While the practitionercan use any set of proscribed or empirical criteria to diagnose thepresence of a psychosis as an indication to practice the methods of theinvention, some illustrative diagnostic guidelines and examples ofrelevant symptoms and conditions are described below.

Psychosis can be diagnosed by formal psychiatric assessment using, forexample, a semi-structured clinical interview described as “TheStructured Clinical Interview for DSM-II-R, or “SCID.” SCID is designedto be administered by clinicians and researchers familiar with thediagnostic criteria used in the DSM-II-R (the revised third edition ofDSM). The SCID has two parts, one for Axis I disorders (clinicaldisorders and other conditions that may be a focus of clinicalattention) and another for Axis II personality disorders (personalitydisorders and mental retardation) (see DSM-IV, supra, pgs 25-31, for ageneral description of a “multi axial assessment system” to guideclinicians in planning treatment and predicting outcome). At the startof the SCID interview, an overview of the present illness, chiefcomplaint, and past episodes of major psychopathology are obtainedbefore systematically asking the patient questions about specificsymptoms. The interview schedule itself has many questions which areopen-ended so that patients have an opportunity to describe symptoms intheir own words.

At the conclusion of the interview, the interviewer also completes theGlobal Assessment of Functioning (GAF) scale, the fifth (“V”) Axis onDSM-IV's multiaxial assessment system. Axis V is for reporting theclinician's judgment of the individual's overall level of functioning.This information is useful in planning treatment and measuring itsimpact, and in predicting outcome. The GAF scale is particularly usefulin tracking the clinical progress of individuals in global terms using asingle measure (see DSM-IV, supra, pages 30 to 31; Kaplan, ed. (1995),supra). In some settings, it may be useful to assess social andoccupational disability and to track progress in rehabilitationindependent of the severity of the psychological symptoms. For thispurpose, use, for example, the proposed Social and OccupationalFunctioning Assessment Scale (SOFAS) DSM-IV, supra, pg. 760, Appendix B.Additional assessment schemes can be used, for example, the GlobalAssessment of Relational Functioning (GARF) Scale (DSM-IV, supra, pg758, Appendix B) or the Defensive Functioning Scale (DSM-IV, supra, pg751, Appendix B).

To assess the progress of a treatment for psychosis or aid in itsdiagnosis or prognosis, the “Brief Psychiatric Rating Scale (BPRS)” canalso be used after the semi-structured interview with the patient. TheBPRS is an 18-dimension rating scale. Each dimension represents a domainof behavior and psychiatric symptoms, such as anxiety, hostility,affect, guilt and orientation. These are rated on a seven-point “LikertScale” from “not present” to “extremely severe.” The BPRS is brief,easily learned and provides a quantitative score that reflects globalpathology. The BPRS is useful in providing a crude barometer of apatient's overall benefit from treatment, and thus is useful inassessing changes in an individual's condition after treatment andamelioration using the methods of the invention (Overall (1962) Psychol.Rep. 10:799; Kaplan (1995), supra).

Objective tests can be also be used with these subjective, diagnosticcriteria to determine whether an individual is psychotic and to measureand assess the success of a particular treatment schedule or regimen.Diagnosis, categorization, or assessment of treatment of psychosis orany psychiatric condition can be objectively assessed using any testknown in the art, such as that described by Wallach (1980) J. Gerontol.35:371-375, or the Stroop Color and Word Test.

The so-called “Wallach Test” can measure the presence and degree ofpsychosis by evaluating cognitive changes in the individual. The testassesses recognition memory, as described above. As discussed in Example1, the Wallach Recognition Test was used to measure the degree ofamelioration of psychosis in the study's subjects.

The Stroop Color and Word Test (“Stroop Test”) is another means toobjectively determine whether an individual is psychotic and to measureefficacy of treatment (see Golden, supra). The Stroop Test candifferentiate between individuals with psychosis and those without.Briefly, the test developed from the observation that the naming ofcolors is always slower than the reading of color names in literateadults. For instance, it always takes less time to read the printed word“yellow” than it does to recognize what color a word is printed in (forexample, “XXX” printed in yellow ink). Furthermore, if color words areprinted in non-matching colored inks (as, the word yellow in red ink),it takes a normal individual 50% longer to name the proper color (red)than if they are shown only the color (such as a red rectangle, or “XXX”in red). This delay in color recognition is called “the color-wordinterference effect” and is the time is the variable parameter measuredin the Stroop Test. The greater the delay, the lower the Stroop Testscore (see also Uttl (1997) J. Clin. Exp. Neuropsychol. 19:405-420).Individuals-with psychosis have statistically significantly lower scoreson the Stroop Test than individuals without psychosis. Importantly,patients with psychotic major depression have statisticallysignificantly lower scores than those with major depression, furtherconfirming the finding that psychotic major depression is a distinctcondition as compared to non-psychotic severe depression.

Psychiatric conditions, such as psychosis, can be further diagnosed andevaluated using any of the many tests or criteria well-known andaccepted in the fields of psychology or psychiatry.

The features (symptoms) of and criteria for diagnosing psychoticdisorders, such as psychotic major depression, are further describedDSM-IV, supra. While the practitioner can use any criteria or means toevaluate whether an individual is psychotic to practice the methods ofthe invention, the DSM-IV sets forth a generally accepted standard forsuch diagnosing, categorizing and treating of psychiatric disorders,including psychosis. Several illustrative examples of such criteriautilized in the methods of the invention are set forth below.

Psychosis is typically characterized as a mental disorder or conditioncausing gross distortion or disorganization of a person's mentalcapacity, affective response, and capacity to recognize reality,communicate, and relate to others to the degree of interfering with hiscapacity to cope with the ordinary demands of everyday life. In acondition or illness involving psychosis, delusions or hallucinationscan be present. The content of the delusions or hallucinations have manydepressive themes. In psychotic major depression there can be“mood-congruent” psychotic features, including, for example, delusionsof guilt, delusions one deserves punishment (e.g. because of a personalinadequacy or moral transgression), nihilistic delusions (e.g. of worldor personal destruction), somatic delusions (e.g. having cancer), ordelusions of poverty. Hallucinations, when present in psychotic majordepression are usually transient and not elaborate and may involvevoices that berate the patient for shortcomings or sins. More rarely,the content of the delusions or hallucinations has no apparentrelationship to depressive themes. In this situation these“mood-incongruent” psychotic features include, for example, grandiosedelusions.

Psychosis can include bipolar I disorder with psychotic features. Theessential feature of this disorder is a clinical course that ischaracterized by the occurrence of one or more manic episodes or mixedepisodes. Often individuals have also had one or more major depressiveepisodes. In addition, the episodes are not better accounted for byschizoaffective disorder and are not superimposed on schizophrenia,schizophreniform disorder, delusional disorder or psychotic disorder nototherwise specified (see DSM-IV, supra, pages 350-352, 320, 328, 333).In bipolar I disorder with psychotic features, delusions orhallucinations, typically auditory, are also present. The content of thedelusions or hallucinations commonly have a manic theme. The featurescan be “mood-congruent” psychotic features, including for exampledelusions that God's voice can be heard explaining the person has aspecial mission or persecutory delusions. More rarely, the content ofthe delusions or hallucinations has no apparent relationship to manicthemes. In this situation these “mood-incongruent” psychotic featuresinclude the same as those described for “mood-congruent” features ofsevere depression with psychotic features.

A condition or illness involving psychosis can also include briefpsychotic disorder, in which one or more of the following symptoms canbe present: delusions, hallucinations, disorganized speech (e.g.frequent derailment or incoherence) and grossly disorganized orcatatonic behavior. Duration of an episode of the disturbance is atleast one day but less than one month.

Psychosis can also be classified as “delusional disorder.” According toDSM IV, diagnostic criteria for delusional disorder includes: nonbizarredelusions of at least one month's duration; criteria A for schizophreniahas never been met, apart from the impact of the delusions; functioningis not markedly impaired; and, behavior is not obviously odd or bizarre.

A condition or illness involving psychosis can be classified as “sharedpsychotic disorder.” According to DSM IV, the diagnostic criteria forshared psychotic disorder includes: a delusion in the context of a closerelationship with another person who has an already-establisheddelusion; the delusion is similar in content to that of the person whoalready has the established delusion; and, the disturbance is not betteraccounted for by another psychotic disorder (e.g. schizophrenia) or amood disorder with psychotic features, and, is not due to the directphysiological effects of a substance or general medical condition.

A condition or illness involving psychosis can be classified as a“substance-induced” psychotic disorder. According to DSM IV criteria,there must be evidence of recent or prolonged substance use, withdrawalfrom a substance or exposure to a toxin. Alternatively, a condition orillness involving psychosis can also be classified as a “psychoticdisorder due to a general medical condition.” According to DSM IVcriteria, there must be: evidence from the history, physical examinationor laboratory findings that the disturbance is the direct physiologicalconsequence of a general medical condition, prominent hallucinations ordelusions, the disturbance is not better accounted for by another mentaldisorder, and, the disturbance does not occur exclusively during thecourse of a delirium.

A condition or illness involving psychosis can be classified as apsychotic disorder not otherwise specified. According to DSM IVcriteria, this category includes psychotic symptomology (i.e. delusions,hallucinations, disorganized speech, grossly disorganized or catatonicbehavior) about which there is inadequate information to make a specificdiagnosis or about which there is contradictory information, ordisorders with psychotic symptoms that do not meet the criteria for anyspecific psychotic disorder. Examples include: postpartum psychosis thatdoes not meet other DSM IV categories; psychotic symptoms that havelasted for less than one month but have not yet remitted; persistentauditory hallucinations in the absence of other features; persistentnonbizarre delusions with period of overlapping mood episodes that havebeen present for a substantial portion of the delusional disturbance;and, situations in which the clinician has concluded that a psychoticdisorder is present but is unable to determine whether it is primary,due to general medical condition or is substance-induced.

b. Assessing and Diagnosing Depression

The psychotic component of psychotic major depression, which haselements of psychosis and depression, is ameliorated by the methods ofthe invention. Other conditions and illnesses with some degrees or formsof depression associated with psychosis are also ameliorated by themethods of the invention. Thus, in practicing some embodiments of theinvention the practitioner should be aware of means to assess anddiagnose depression. Such criteria are well known in the art, and someillustrative examples are set forth below.

Diagnosis of depression can be assisted by formal psychiatric assessmentusing a structured interview instrument like the SCID (discussed above),as well as a measure of the degree of depressive symptoms, such as, forexample, the Hamilton Rating Scale for Depression (“HAM-D”) (Hamilton(1962) J. Neurol. Psychiatry 23:56-62, Avery (1979) Am. J. Psychiatry135:559-562), a widely used scale. The HAM-D is scored on the basis of asemistructured interview. The patient is rated on depression-relatedsymptoms, including psychomotor retardation, insomnia, mood and insight.Several forms of depression with different numbers of symptoms ratingsexist, leading to some confusion. However, the combined score correlateshighly with the degree of depression severity. The rating scale iseffective in monitoring a depressed state over time and is useful as anindex of treatment effectiveness. The Hamilton Rating Scale can be usedwith an additional assessment device that focuses on the mood,affective, and cognitive changes known to accompany major depression(Kaplan, et al., (1995), supra).

As with psychosis, the “Brief Psychiatric Rating Scale (BPRS)” can alsobe used to diagnose or evaluate the efficacy of a treatment fordepression in conjunction with the semi-structured interview. The BPRSis useful in providing a crude barometer of a patient's overall benefitfrom treatment, and thus is useful in assessing changes in anindividual's condition after treatment and amelioration using themethods of the invention (Overall (1962) supra; Kaplan (1995), supra).Also as with psychosis, depression-can be assessed by evaluatingcognitive changes using any test known in the art, such as thatdescribed by Wallach (1980) J. Gerontol. 35:371-375. The so-called“Wallach Test” assesses recognition memory. Psychiatric conditions, suchas depression, can be further diagnosed and evaluated using any of themany tests or criteria well-known and accepted in the fields ofpsychology or psychiatry.

c. Assessing and Diagnosing Schizoaffective Disorder

The psychotic component of schizoaffective disorder is ameliorated bythe methods of the invention. The diagnostic criteria forschizoaffective disorder includes: an uninterrupted period of illnessduring which, at some time, there is either a major depressive episode,a manic episode or a mixed episode concurrent with symptoms that meetthe criteria for schizophrenia. In schizoaffective disorder there mustbe: a mood episode that is concurrent with the active-phase symptoms ofschizophrenia; mood symptoms must be present for a substantial portionof the total duration of the disturbance; and, delusions orhallucinations must be present for at least two weeks in the absence ofprominent mood symptoms. In contrast, mood symptoms in schizophreniaeither have a duration that is brief relative to the total duration ofthe disturbance, occur only during the prodromal or residual phases, ordo not meet full criteria for a mood episode. The diagnostic criteriafor schizophrenia include characteristic symptoms, social oroccupational dysfunction, and/or persistence of symptoms. The“schizophrenia” criteria for schizoaffective disorder can also beclassified as “schizophreniform disorder,” which is diagnosed if the DSMIV criteria A, D and E of schizophrenia are met. An episode of thisdisorder lasts at least one month but less than six months. See also:Sharma (1997) Am. J. Psychiatry 154:1019-1021; McElroy (1991) J. Clin.Psychiatry 52:411-414.

The “Brief Psychiatric Rating Scale (BPRS)” can also be used after thesemi-structured interview with the patient to evaluate schizophrenia anddistinguish it from schizophreniform disorder (SD) and the psychosisassociated with SD, as treated by the methods of the invention (Overall(1962) supra; Kaplan (1995), supra). It can be used to access changes incondition after treatment and amelioration when utilizing the methods ofthe invention (Kaplan (1995), supra).

d. Diagnosing and Assessing Alzheimer's Disease Related Psychosis

Psychosis associated with senile dementias and Alzheimer's disease isameliorated by the methods of the invention. Behavioral changes arecommon in Alzheimer's disease and include psychosis, agitation,depression, anxiety, personality alterations, and neurovegetativechanges. See Engelborghs (1997) Acta Neurol. Belg. 97:67-84; Cummings(1996) Neurology 47:876-883; Samnson (1996) Eur. Neurol. 36:103-106.

Criteria to assess and diagnose psychosis associated with Alzheimer'sDisease are the same as those used for psychosis, as described inSection 3.a, above.

e. Diagnosing and Assessing Drug-Related Psychosis

Psychosis associated with substance abuse or psychosis as a side-effectof medication is ameliorated by the methods of the invention. Forexample, psychosis is associated with cocaine abuse and addiction. Thus,the GR antagonists of the invention, such as mifepristone, can be usedas a treatment for cocaine-induced psychosis. In another embodiment, themethods of the invention can treat cannabis-induced chronic psychosis,see Longhurst (1997) Aust. N. Z. J. Psychiatry 31:304-305. See alsoEvans (1997) “Drug induced psychosis with doxazosin,” B M J 314: 1869;Bhatia (1996) “Chloroquine—induced recurrent psychosis,” Indian J. Med.Sci. 50:302-304; Scurlock (1996) “Another case of nicotine psychosis”Addiction 91:1388; Cohen (1996) “Substance-induced psychosis” Br. J.Psychiatry 168:651-652; Popli (1997) “Sertraline and psychotic symptoms:a case series,” Ann. Clin. Psychiatry 9:15-17; Schreiber (1997)“Metronidazole-induced psychotic disorder,” Am. J. Psychiatry154:1170-1171.

Criteria to assess and diagnose psychosis associated with drug abuse anddrug addiction are the same as those used for psychosis, as described inSection 3.a, above.

f. Other Psychosis-Associated Conditions

The anti-psychotic GR antagonists and methods of the invention can beeffective in treating psychotic aggressive patients, conduct-disorderedchildren, and mentally retarded patients. See Fava (1997) Psychiatr.Clin. North Am. 20:427-451. In another embodiment, the methods of theinvention can be used as a adjunct in treating AIDS patients withpsychiatric disorders, as psychosis secondary to AIDS infection iscommon (see Susser (1997) Am. J. Psychiatry 154:864-866; Schiff(1997) N.Engl. J. Med. 336:1190). In another embodiment, the methods of theinvention can be used to treat psychosis associated with Parkinson'sdisease. Many patients with Parkinson's disease and dementia experiencepsychosis and psychotic symptoms. In Parkinson's disease, dementia isassociated with major behavioral, cognitive, and functional problems(Naimark (1996) “Psychotic symptoms in Parkinson's disease patients withdementia.” J. Am. Geriatr. Soc. 44:296-299. Means to diagnose theseconditions are well known in the art and are described in thesereferences and other relevant texts.

4. Treatmant of Conditions and Illnesses Associated with Psychosis UsingGlucocorticoid Receptor Antagonists

Antiglucocorticoids, such as mifepristone, are formulated aspharmaceuticals to be used in the methods of the invention. Anycomposition or compound that can block a biological response associatedwith the binding of cortisol or a cortisol analogue to a GR can be usedas a pharmaceutical in the invention. Routine means to determine GRantagonist drug regimens and formulations to practice the methods of theinvention are well described in the patent and scientific literature,and some illustrative examples are set forth below.

a. Glucocorticoid Receptor Antagonists as Pharmaceutical Compositions

The GR antagonists used in the methods of the invention can beadministered parenterally, topically, orally, or by localadministration, such as by aerosol or transdermally. The methods of theinvention provide for prophylactic and/or therapeutic treatments. The GRantagonists as pharmaceutical formulations can be administered in avariety of unit dosage forms depending upon the condition or disease andthe degree of psychosis, the general medical condition of each patient,the resulting preferred method of administration and the like. Detailson techniques for formulation and administration are well described inthe scientific and patent literature, see, for example, the latestedition of “Remington's Pharmaceutical Sciences” (Maack Publishing Co,Easton Pa.).

GR antagonist pharmaceutical formulations can be prepared according toany method known to the art for the manufacture of pharmaceuticals. Suchdrugs can contain sweetening agents, flavoring agents, coloring agentsand preserving agents. Any GR antagonist formulation can be admixturedwith nontoxic pharmaceutically acceptable excipients which are suitablefor manufacture.

Pharmaceutical formulations for oral administration can be formulatedusing pharmaceutically acceptable carriers well known in the art indosages suitable for oral administration. Such carriers enable thepharmaceutical formulations to be formulated in unit dosage forms astablets, pills, powder, dragees, capsules, liquids, lozenges, gels,syrups, slurries, suspensions, etc., suitable for ingestion by thepatient. Pharmaceutical preparations for oral use can be obtainedthrough combination of GR antagonist compounds with a solid excipient,optionally grinding a resulting mixture, and processing the mixture ofgranules, after adding suitable additional compounds, if desired, toobtain tablets or dragee cores. Suitable solid excipients arecarbohydrate or protein fillers include, but are not limited to sugars,including lactose, sucrose, mannitol, or sorbitol; starch from corn,wheat, rice, potato, or other plants; cellulose such as methylcellulose, hydroxypropylmethyl-cellulose, or sodiumcarboxymethylcellulose; and gums including arabic and tragacanth; aswell as proteins such as gelatin and collagen. If desired,disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragee cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations of theinvention can also be used orally using, for example, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and acoating such as glycerol or sorbitol. Push-fit capsules can contain GRantagonist mixed with a filler or binders such as lactose or starches,lubricants such as talc or magnesium stearate, and, optionally,stabilizers. In soft capsules, the GR antagonist compounds may bedissolved or suspended in suitable liquids, such as fatty oils, liquidparaffin, or liquid polyethylene glycol with or without stabilizers.

Aqueous suspensions of the invention contain a GR antagonist inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethylene oxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol (e.g.,polyoxyethylene sorbitol mono-oleate), or a condensation product ofethylene oxide with a partial ester derived from fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Oil suspensions can be formulated by suspending a GR antagonist in avegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oil suspensionscan contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents can be added to provide a palatable oralpreparation. These formulations can be preserved by the addition of anantioxidant such as ascorbic acid. As an example of an injectable oilvehicle, see Minto (1997) J. Pharmacol. Exp. Ther. 281:93-102.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water can beformulated from a GR antagonist in admixture with a dispersing,suspending and/or wetting agent, and one or more preservatives. Suitabledispersing or wetting agents and suspending agents are exemplified bythose disclosed above. Additional excipients, for example sweetening,flavoring and coloring agents, can also be present.

The pharmaceutical formulations of the invention can also be in the formof oil-in-water emulsions. The oily phase can be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan mono-oleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. Theemulsion can also contain sweetening and flavoring agents. Syrups andelixirs can be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations can also contain a demulcent, apreservative, a flavoring or a coloring agent.

The GR antagonist pharmaceutical formulations of the invention can be inthe form of a sterile injectable preparation, such as a sterileinjectable aqueous or oleaginous suspension. This suspension can beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation can also be a sterile injectablesolution or suspension in a nontoxic parenterally-acceptable diluent orsolvent, such as a solution of 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are water and Ringer'ssolution, an isotonic sodium chloride. In addition, sterile fixed oilscan conventionally be employed as a solvent or suspending medium. Forthis purpose any bland fixed oil can be employed including syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid canlikewise be used in the preparation of injectables.

The GR antagonists of this invention can also be administered in theform of suppositories for rectal administration of the drug. Theseformulations can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperatures and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

They can also be administered by in intranasal, intraocular,intravaginal, and intrarectal routes including suppositories,insufflation, powders and aerosol formulations (for examples of steroidinhalants, see Rohatagi (1995) J. Clin. Pharmacol. 35:1187-1193; Tjwa(1995) Ann. Allergy Asthma Immunol. 75:107-111).

Products of the invention which are preferably administered by thetopical route can be administered as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols. The GR antagonists of the invention, suchas mifepristone, can be delivered by transdermally or via intradermalinjection of drug (mifepristone)-containing microspheres, which slowlyrelease subcutaneously (see Rao (1995) J. Biomater Sci. Polym. Ed.7:623-645; for biodegradable and injectable gel formulations see Gao(1995) Pharm. Res. 12:857-863 (1995); for use of microspheres for oraladministration, see Eyles (1997) J. Pharm. Pharmacol. 49:669-674). Bothtransdermal and intradermal routes afford constant delivery for weeks ormonths.

The GR antagonist pharmaceutical formulations of the invention can beprovided as a salt and can be formed with many acids, including but notlimited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic,succinic, etc. Salts tend to be more soluble in aqueous or otherprotonic solvents that are the corresponding free base forms. In othercases, the preferred preparation may be a lyophilized powder in 1 mM-50mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to5.5, that is combined with buffer prior to use.

In another embodiment, the GR antagonist formulations of the inventionare useful for parenteral administration, such as intravenousadministration or administration into a body cavity or lumen of anorgan. The formulations for administration will commonly comprise asolution of the mifepristone dissolved in a pharmaceutically acceptablecarrier, preferably an aqueous carrier. A variety of aqueous carrierscan be used, e.g., buffered saline and the like. These solutions aresterile and generally free of undesirable matter. These formulations maybe sterilized by conventional, well known sterilization techniques. Theformulations may contain pharmaceutically acceptable auxiliarysubstances as required to approximate physiological conditions such aspH adjusting and buffering agents, toxicity adjusting agents and thelike, for example, sodium acetate, sodium chloride, potassium chloride,calcium chloride, sodium lactate and the like. The concentration of GRantagonist in these formulations can vary widely, and will be selectedprimarily based on fluid volumes, viscosities, body weight and the likein accordance with the particular mode of administration selected andthe patient's needs.

In another embodiment, the GR antagonist formulations of the inventioncan be delivered by the use of liposomes which fuse with the cellularmembrane or are endocytosed, i.e., by employing ligands attached to thelipqsome, or attached directly to the oligonucleotide, that bind tosurface membrane protein receptors of the cell resulting in endocytosis.By using liposomes, particularly Where the liposome surface carriesligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of the GRantagonist into the target cells in vivo. See Al-Muhammed (1996) J.Microencapsul. 13:293-306; Ostro (1989) Am. J. Hosp. Pharm.46:1576-1587.

b. Determining Dosing Regimens for Glucocorticoid Receptor Antagonists

The methods of the invention ameliorate psychosis, i.e., prevent, slowthe onset of, decrease the frequency of, diminish the severity of orcure a psychosis and/or its complications. The amount of GR antagonistadequate to accomplish this is defined as a “therapeutically effectivedose.” The dosage schedule and amounts effective for this use, i.e., the“dosing regimen,” will depend upon a variety of factors, including thestage of the disease or condition, the severity of the disease orcondition, the general state of the patient's health, the patient'sphysical status, age and the like. In calculating the dosage regimen fora patient, the mode of administration also is taken into consideration.

The dosage regimen must also take into consideration thepharmacokinetics, i.e., the GR antagonists' rate of absorption,bioavailability, metabolism, clearance, and the like (see, for example,Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617;Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995)Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108;the latest Remington's, supra). In one study, less than 0.5% of thedaily dose of mifepristone was excreted in the urine; the drug boundextensively to circulating albumin (see Kawai (1989) supra).

The state of the art allows the clinician to determine the dosageregimen for each individual patient, GR antagonist and disease orcondition treated. As an illustrative example, the guidelines providedbelow for mifepristone can be used as guidance to determine the dosageregiment, i.e., dose schedule and dosage levels, of any GR antagonistadministered when practicing the methods of the invention.

Single or multiple administrations of mifepristone formulations may beadministered depending on the dosage and frequency as required andtolerated by the patient. The formulations should provide a sufficientquantity of mifepristone to effectively ameliorate the psychosis. Thus,a typical pharmaceutical formulations for oral administration ofmifepristone would be about 8 to 20 mg/kg of body weight per patient perday. Dosages from about 2 mg to about 30-mg per kg of body weight perpatient per day may be used, particularly when the drug is administeredto an anatomically secluded site, such as the cerebral spinal fluid(CSF) space, in contrast to administration orally, into the bloodstream, into a body cavity or into a lumen of an organ. Substantiallyhigher dosages are possible in topical administration. Actual methodsfor preparing parenterally administrable GR antagonist formulations willbe known or apparent to those skilled in the art and are described inmore detail in such publications as Remington's Pharmaceutical Science,15th ed., Maack Publishing Company, Easton, Pa. (1980). In a preferredembodiment of the invention, the invention provide for a method oftreating psychosis by administering mifepristone in a daily amount ofabout 8 to 12 mg per kilogram of body weight per day. Using this dosage,the administration can continue for a period of about four days.Alternatively, in another embodiment the mifepristone is administered ina daily amount of about 600 mg per day. See also Nieman, In “ReceptorMediated Antisteroid Action,” Agarwal, et al., eds., De Gruyter, N.Y.(1987).

After a pharmaceutical comprising a GR antagonist of the invention hasbeen formulated in a acceptable carrier, it can be placed in anappropriate container and labeled for treatment of an indicatedcondition. For administration of GR antagonists, such labeling wouldinclude, for example, instructions concerning the amount, frequency andmethod of administration. In one embodiment, the invention provides fora kit for the amelioration of psychosis in a human which includes aglucocorticoid receptor antagonist and instructional material teachingthe indications, dosage and schedule of administration of theglucocorticoid receptor antagonist. When mifepristone is the GRantagonist used, the instructional material indicates that the GRantagonist can be used for in a daily amount of about 8 to 12 mg perkilogram of body weight per day, and, the administration of theglucocorticoid receptor antagonist continues for period of about fourdays.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims.

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Example 1 Treating Psychotic Major Depression with Mifepristone

The following example details studies which demonstrate that the methodof the invention is an effective treatment for psychosis.

Study Background

This study demonstrates that a glucocorticoid receptor antagonist,mifepristone, administered in dosages of about 10 mg per kg per day overa relatively short treatment period, is an effective treatment forpsychotic major depression. The basic strategy was to demonstrate thathigh dose mifepristone, in the range of 600 mg per day, over arelatively short period of time—about four days—is an effectivetreatment for psychotic major depression. The study requires a nine day,closely observed hospital stay.

Patient Selection

Individuals included in this study were diagnosed as psychoticdepressives using criteria as set forth by the DSM-IV, as describedabove. This diagnosis was confirmed by two psychiatrists. All arebetween the ages of 18 and 75. Apart from hypercortisolemia, they haveno major medical problems. They have no signs of Cushings Syndrome. Nochildren of childbearing potential are included in the study.Individuals admitting to having used illicit drugs within a month priorto admission for the study are excluded. Individuals admitting todrinking in excess of two ounces of alcohol daily are excluded from thestudy. No anti-psychotic medication was taken within three days ofentering the study. While, concurrent anti-depressant was not a criteriaused to excluded anyone from the study, no individual was started on ananti-depressant medication while participating in the study. Allpatients gave their written consent to a protocol approved by the HumanSubjects Committee at Stanford University Medical Center.

All participants were given the Hamilton Rating Scale for Depression(HAM-D, Hamilton (1962) J. Neurol. Psychiatry, supra, discussed above)and the Structured Clinical Interview for DSM-IV Axis I mood disorderstests (as described above). Only individuals with a score greater than21 on the HAM-D test continued in the study (a HAM-D score of >21indicates moderate to severe depression). The HAM-D Rating Scale wasalso given after administration of mifepristone, as described below.

On the basis of these criteria, sixteen (16) individuals with psychoticmajor depression were selected.

Measuring Blood Cortisol Levels

The “Double Antibody Cortisol Kit™” (Diagnostic Products Corporation,Los Angeles, Cali.) was used to measure blood cortisol levels. This testis a competitive radioimnunoassay in which ¹²⁵I-labeled cortisolcompetes with cortisol from an clinical sample for antibody sites, andwas performed essentially according to manufacturer's instructions usingreagents supplied by manufacturer.

Briefly, blood was collected by venipuncture and serum separated fromthe cells. The samples were stored at 2 to 8° C. for up to seven days,or up to two month frozen at −20° C. Before the assay, samples wereallowed to come up to room temperature (15-28° C.) by gentle swirling orinversion. Sixteen tubes in duplicate at 25 microliters of serum pertube was prepared. Cortisol concentrations were calculated from theprepared calibration tubes. Net counts equaled the average CPM minus theaverage non-specific CPM. Cortisol concentrations for the unknowns wereestimated by interpolation from the calibration curve (Dudley, et al.(1985) Clin. Chem. 31:1264-1271).

Assessing Amelioration of Psychosis

Formal psychiatric assessment, including the HAM-D rating scale (Overall(1962) supra; Kaplan (1995), supra, discussed above), the BriefPsychiatric Rating Scale (BPRS) (Overall (1962) supra; Kaplan (1995),supra, discussed above) and the Clinical Global Impression (GAF)evaluation (DSM-IV, supra, pages 30 to 31; Kaplan, ed. (1995), supra)was carried out on days one, three, five, seven and nine of the study at10:00 AM (at 1000 hours). A paragraph recall test (see below) was givenat 11:30 AM (at 1130 hours) on days one, five and nine. Cortisol levelswere measured serially every half hour from 1:30 to 4:00 PM (1300 to1600 hours) on days one, five and nine. Plasma ACTH and Plasma HVA wasmeasured serially every hour from 1300 to 1600 on days one, five andnine. Routine biological and hematological studies were conducted daily,particularly to screen for evidence of relative adrenal insufficiency,i.e., hypoglycemia, eosinophilia.

One means used to assess/measure improvement, or amelioration ofpsychosis in the study was the “Wallach Recognition Test” (a paragraphrecall test). Newly evaluated individuals with an initial diagnosis ofpsychotic major depression, diagnosed as described above, were given arecognition task adapted from Wallach (1980) supra. Subjects listened toa taped recording of a sixteen-word list presented at the rate of oneword every ten seconds. The-subject repeats each of the sixteen wordsand is asked to think of what the words mean to them. Following thepresentation of the list, the subject engages in a twenty minute motordistraction task. The subject then listens to a fifty-word listcontaining the sixteen original target words plus thirty-four backgrounddistraction words. The subject then is asked to discern between targetwords and distractors.

Dosage Regimen and Administration of Mifepristone

Sixteen newly admitted patients with an admitting diagnosis of psychoticmajor depression confirmed by two psychiatrists were enrolled in thestudy. Each patient conformed with all of the above described criteria.The subject is given either: 600 milligrams of mifepristone per dayorally, in one dose, over four days, followed by four days of placebo;or, four days of placebo followed by the same dose and regimen ofmifepristone (patients serving as their own control in this “cross-over”study). In the patients administered mifepristone, three two hundredmilligram tablets per day were given for four days. The mifepristone(RU486) tablets were supplied by The Population Council and RousselUclaf, Hoechst Marion Roussel USA, Kansas City, Mo. The tablets weremanufactured by Shanghai HuaLian Pharmaceuticals Co., Ltd., Shanghai,China (currently the sole commercial source of RU486).

Both patients and the investigators are “blind” as to which compound(test mifepristone or placebo) the patient received.

Results

The protocol has been competed for three patients. While the study is adouble-blind placebo controlled study, and to date the blind has notbeen broken, two preliminary observations can be made. First, eachsubject receiving mifepristone as described above showed a significantimprovement in their psychiatric condition. Second, no adverse effectswere subjectively reported by the patient or objectively observed byraters or staff.

When the Wallach Recognition Test was used to measure the degree ofamelioration of psychosis in the study's subjects, all individuals whoreceived mifepristone showed an amelioration of their psychosis. On theaverage, the number of times test subjects perceived distracters aswords they had actually heard before (in the test's tape recording)declined between 25% and 100% after treatment.

On the average HAM-D scores declined from about 26 to about 13.5. BriefPsychiatric Rating Scale (BPRS) scores declined from about 40.5 to about29.5.

Clinical Global Impression (CGI scale, based on a GAF evaluation,discussed above, see DSM-IV, supra, pages 30 to 31; Kaplan, ed. (1995))scores dropped from about 5 (indicating “markedly depressed”) to about 3(“mildly depressed”). As discussed above, the GAF scale is particularlyuseful in tracking the clinical progress of individuals in global termsusing a single measure.

These data demonstrate that high dose mifepristone, in the range of 600mg per day, over a relatively short period of time—about four days—is aneffective and safe treatment for psychotic major depression.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims.

What is claimed is:
 1. A method of ameliorating psychosis associatedwith cocaine addiction in a patient in need thereof by administration ofan amount of a glucocorticoid receptor antagonist effective toameliorate the psychosis, with the proviso that the patient not besuffering from Cushing's Syndrome and the psychosis is associated withcocaine addiction.
 2. The method of claim 1, wherein the glucocorticoidreceptor antagonist comprises a steroidal skeleton with at least onephenyl-containing moiety in the 11-beta position of the steroidalskeleton.
 3. The method of claim 2, wherein the phenyl-containing moietyin the 11-beta position of the steroidal skeleton is adimethylaminophenyl moiety.
 4. The method of claim 2, wherein theglucocorticoid receptor antagonist comprises mifepristone.
 5. The methodof claim 2, wherein the glucocorticoid receptor antagonist is selectedfrom the group consisting of RU009 and RU044.
 6. The method of claim 1,wherein the glucocorticoid receptor antagonist is administered in adaily amount of between about 8 to 20 mg per kilogram of body weight perday.
 7. The method of claim 1, wherein the glucocorticoid receptorantagonist is administered in a daily amount of about 8 to 12 mg perkilogram of body weight per day.
 8. The method of claim 1, wherein theglucocorticoid receptor antagonist is administered for about four days.9. The method of claim 1, wherein the glucocorticoid receptor antagonistis administered in a daily amount of about 600 mg per day.
 10. Themethod of claim 1, wherein the administration is once per day.
 11. Themethod of claim 1, wherein the mode of administration is oral.
 12. Themethod of claim 1, wherein the mode of administration is transdermal.